Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment

Abstract

The water channel aquaporin-2 (AQP2), expressed in the kidney collecting ducts, plays a pivotal role in maintaining body water balance. The channel is regulated by the peptide hormone arginine vasopressin (AVP), which exerts its effects through the type 2 vasopressin receptor (AVPR2). Disrupted function or regulation of AQP2 or the AVPR2 results in nephrogenic diabetes insipidus (NDI), a common clinical condition of renal origin characterized by polydipsia and polyuria. Over several years, major research efforts have advanced our understanding of NDI at the genetic, cellular, molecular, and biological levels. NDI is commonly characterized as hereditary (congenital) NDI, arising from genetic mutations in the AVPR2 or AQP2; or acquired NDI, due to for exmple medical treatment or electrolyte disturbances. In this article, we provide a comprehensive overview of the genetic, cell biological, and pathophysiological causes of NDI, with emphasis on the congenital forms and the acquired forms arising from lithium and other drug therapies, acute and chronic renal failure, and disturbed levels of calcium and potassium. Additionally, we provide an overview of the exciting new treatment strategies that have been recently proposed for alleviating the symptoms of some forms of the disease and for bypassing G protein-coupled receptor signaling.

Figures

Figure 1.

Illustration of AVP-mediated trafficking of AQP2 in the principal cell of the kidney collecting duct. Upon binding of AVP to the basolateral G protein-coupled vasopressin receptor AVP2R (V2R), Gs protein-mediated signaling leads to activation of adenylate cyclase (AC). This activation results in increased levels of intracellular cAMP, activation of PKA, and subsequent AQP2 phosphorylation and AQP2 accumulation in the apical plasma membrane of the cell. This event renders the cell permeable to water via the apically located AQP2 and the basolaterally located aquaporins, AQP3 and AQP4.

Figure 2.

Four fundamental causes and some of the underlying mechanisms of DI. Central DI is due to inadequate production/secretion of AVP in the posterior pituitary. Gestational diabetes is due to increased metabolism of AVP by the placenta during pregnancy. Thus, both central and gestational forms of DI are due to reduced levels of AVP and are distinguished on a clinical basis. NDI is caused by defects in the kidney preventing concentration of urine in response to AVP. Finally, primary dipsogenic DI is due to excessive water intake leading to suppression of AVP release.

Figure 3.

The human AVP gene. The gene is composed of three exons and two introns. This gene gives rise to a precursor prepro-AVP peptide in magnocellular neurons of the hypothalamus, which is converted to pro-AVP by removal of the signal peptide and addition of carbohydrate side chains in the ER. The final AVP peptide is nine amino acids in length. VP, AVP; NP, AVP-associated NPII; CP, glycosylated protein, copeptin; SP, signal peptide.

Figure 4.

A schematic diagram of the vasopressin receptor (AVP2R) in the cell plasma membrane. Some of the mutations causing NDI are indicated. Some mutations, such as splicing, complex rearrangements, gross deletions, and insertions, are not illustrated.

Figure 5.

A schematic presentation of AQP2 in the membrane with indications of some of the mutations known to cause DI. Some mutations, such as splicing, are not indicated in the figure.

Figure 6.

Schematic presentation of various potential strategies for treating NDI. A, Rescue of plasma membrane expression of the AVP2R (V2R) in NDI by cell-permeable antagonists. Antagonists (red circles) can enter the cell and bind to a class II mutant V2R that is misfolded in the rough ER (RER). This aids stabilization of the protein conformation and allows the V2R to escape the RER and Golgi and reach the cell plasma membrane. In the plasma membrane, the antagonist is displaced by AVP (green circles) and normal signaling occurs, leading to increased cAMP and AQP2 trafficking. B, Activation of mutated and misfolded V2R by cell-permeable agonists. The agonists (blue circles) enter the cell and reach the misfolded V2R in the RER. This allows normal signaling to occur, leading to increased cAMP and AQP2 trafficking. C, Rescue of mutant V2R plasma membrane expression and signaling via cell-permeable agonists. This class of agonists (yellow circles) enter the cell and aid proper folding of the V2R in the RER, which results in rescue of the V2R to the plasma membrane. The compounds secondarily act as agonists and induce normal V2R signaling from the plasma membrane. D, Mechanisms to bypass V2R signaling and allow translocation of AQP2 to the plasma membrane. 1, EP2 and EP4 prostanoid receptor agonists have been shown to induce membrane expression and/or abundance of AQP2; 2, increased abundance of cGMP via PDE5 inhibitors or cGMP addition has been shown to induce AVP independent AQP2 trafficking to the plasma membrane; 3, increasing cAMP levels via prevention of cAMP degradation leads to activation of PKA and subsequently AQP2 membrane insertion; 4, AQP2 membrane accumulation can be increased by preventing AQP2 internalization (one class of compounds suggested to work via this effect are statins); and 5, inhibition of the molecular chaperone Hsp90 partially allows escape of misfolded AQP2 from the RER to the plasma membrane, where it retains some of its water transport properties.